title: Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32.
abstract: Infection with the bacterial pathogen Mycobacterium tuberculosis imposes an enormous burden on global public health. New antibiotics are urgently needed to combat the global tuberculosis pandemic; however, the development of new small molecules is hindered by a lack of validated drug targets. Here, we describe the identification of a 4,6-diaryl-5,7-dimethyl coumarin series that kills M. tuberculosis by inhibiting fatty acid degradation protein D32 (FadD32), an enzyme that is required for biosynthesis of cell-wall mycolic acids. These substituted coumarin inhibitors directly inhibit the acyl-acyl carrier protein synthetase activity of FadD32. They effectively block bacterial replication both in vitro and in animal models of tuberculosis, validating FadD32 as a target for antibiotic development that works in the same pathway as the established antibiotic isoniazid. Targeting new steps in well-validated biosynthetic pathways in antitubercular therapy is a powerful strategy that removes much of the usual uncertainty surrounding new targets and in vivo clinical efficacy, while circumventing existing resistance to established targets.
authors.affiliation: Infectious Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Stanley
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kawate
authors.forename: Noriaki
authors.initials: N
authors.lastname: Iwase
authors.forename: Motohisa
authors.initials: M
authors.lastname: Shimizu
authors.forename: Anne E
authors.initials: AE
authors.lastname: Clatworthy
authors.forename: Edward
authors.initials: E
authors.lastname: Kazyanskaya
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ioerger
authors.forename: Noman A
authors.initials: NA
authors.lastname: Siddiqi
authors.forename: Shoko
authors.initials: S
authors.lastname: Minami
authors.forename: John A
authors.initials: JA
authors.lastname: Aquadro
authors.forename: Sarah Schmidt
authors.initials: SS
authors.lastname: Grant
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Rubin
authors.forename: Deborah T
authors.initials: DT
authors.lastname: Hung
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000187:drug effects* / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D009171:Mycolic Acids / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D001426:Bacterial Proteins; D003374:Coumarins; D009171:Mycolic Acids